The present invention relates to a pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA (percutaneous transluminal coronary angioplasty)/PTCR (percutaneous transluminal coronary revascularization)/CABG (coronary artery bypass grafting) etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery, and also symptoms derived from seizures, epilepsy, migraine, etc. and Ca2+ overload suppressants. The present invention further relates to a novel arylpiperidinol and arylpiperidine derivatives having an action in suppressing Ca2+ overload and useful for the alleviation or treatment of symptoms due to the above ischemic diseases and also symptoms derived from seizures, epilepsy, migraine, etc., their pharmaceutically acceptable salts, and synthetic intermediates for the preparation of the aforementioned compounds.
In cellular disorders caused by advanced ischemia, the depletion of ATP, the fall in the pH in the cells, and the destruction of the mechanism for maintenance of the energy-dependent ion homeostasis inside and outside the cell cause the accumulation of a large amount of intracellular divalent Ca ions (Ca2+). It is believed that the Ca2+ overload causes functional disorders in the mitochondria and randomly activates various enzyme reactions and invites further Ca2+ overload to cause a repeated vicious cycle and in the end causes irreparable damage to the cell wall and cell death [F. B. Meyer: Brain Res. Rev., 14, 227 (1989); E. Boddeke et al.: Trends Pharmacol. Sci., 10,397 (1989)].
Pharmaceuticals which suppress cytotoxic Ca2+ overload are considered to be these for the alleviation or treatment of various ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery.
Under the above circumstances, the objective of the present invention is to provide a pharmaceutical composition having an action of suppressing cytotoxic Ca2+ overload, with high safety, and useful for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine.
Another objective of the present invention is to provide a novel arylpiperidinol and arylpiperidine derivatives useful as pharmaceutical ingredients, their pharmaceutically acceptable salts, and synthetic intermediates of the same.
In accordance with the present invention, there is provided a pharmaceutical composition for the alleviation or treatment of symptoms due to ischemic diseases or symptoms derived from seizures, epilepsy, and migraine containing, as an effective ingredient, a compound having the formula (I): 
wherein, R is a hydrogen atom, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted benzoyl group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxy group or a group xe2x80x94NHCO(CH2)nxe2x80x94, where n is an integer of 1 to 5, E is a connecting bond, an oxygen atom, or a methylene group, X is a hydroxyl group or a hydrogen atom provided that, when E is an oxygen atom or a methylene group, X is not a hydrogen atom, and Y and Z may be the same or different from each other and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom or its pharmaceutically acceptable salt.
The present inventors screened compounds by evaluating the inhibitory effects on the non-L-type Ca2+ channel and Na+ channel reported to be involved in the mechanism of cause of Ca2+ overload [P. J. Pauwels et al.; Life Science, 48, 1881 (1991)]. As a result, it was found that the compounds having the formula (I) have a powerful action in suppressing one type of the non-L-type Ca2+ channel, that is, the T-type Ca2+ channel, and Na+ channel and was effective in various types of animal disease models as well, whereby the present invention was completed.
In the present invention, as ischemic diseases, cerebral ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other functional and organic diseases of the brain, ischemic cardiac diseases, for example, variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and other myocardial ischemia-reperfusion injury, and also disorders of transplanted organs at the time of organ transplants, and temporary blockage of the blood flow in organs at the time of surgery may be mentioned.
The compounds having the formula (I) according to the present invention include compounds having the formulas (Ia) and (Ib):
In the formula (Ia) 
wherein, R, A, B, E, Y, and Z are as the same defined above, examples of the preferable substituent of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted benzoyl group represented by R, include a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom, a hydroxyl group, a C1 to C5 optionally branched alkoxy group such as a methoxy group and an ethoxy group, and a C1 to C5 optionally branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of the halogen atom of the C1 to C5 optionally branched alkyl group optionally substituted with a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, etc.
Examples of the cycloalkylene group represented by A in formula (Ia) include preferably a C3 to C6 cycloalkylene group such as a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,1-cyclopentylene group, and a 1,1-cyclohexylene group, more preferably a 1,1-cyclopropylene group or a 1,2-cyclopropylene group. Preferable examples of the alkenylene group of the alkenylene group optionally substituted with a lower alkyl group include preferably a C2 to C4 alkenylene group such as a vinylene group and a butadiene group, more preferably a butadiene group. Examples of the alkyl groups of the alkenylene group optionally substituted with a lower alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
Preferable examples of the alkylene group of the alkylene group optionally substituted with a hydroxy group or an alkoxy group represented by B in formula (Ia) include preferably a C1 to C6 optionally branched alkylene group such as a methylene group, a dimethylene group, a trimethylene group, a tetramethylene group, a methylmethylene group, and a cyclopropylmethylene group, more preferably a methylene group, a dimethylene group, a trimethylene group, a tetramethylene group, and a cyclopropylmethylene group. Preferable examples of the alkoxy group of the alkylene group optionally substituted with an alkoxy group include a C1 to C5 optionally branched alkoxy group such as a methoxy group and an ethoxy group. Further, the integer n of 1 to 5 of the group xe2x80x94NHCO(CH2)nxe2x80x94 is preferably 1 or 3.
Preferable examples of the halogen atom represented by Y or Z in formula (Ia) include a fluorine atom, a chlorine atom, and a bromine atom. Preferable examples of the alkoxy group include a C1 to C5 optionally branched alkoxy group such as a methoxy group and an ethoxy group. Preferable examples of the alkyl group optionally substituted with a halogen atom include a C1 to C5 optionally branched alkyl group such as a methyl group, an ethyl group, and a trifluoromethyl group. Examples of the halogen atom of an alkyl group optionally substituted with a halogen atom include a fluorine atom, a chlorine atom and a bromine atom.
In the formula (Ib) 
wherein, R, A, B, Y, and Z are the same as defined above, examples of the preferable substituent of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted benzoyl group represented by R include a halogen atom such as a fluorine atom a chlorine atom and a bromine atom, a hydroxyl group, a C1 to C5 optionally branched alkoxy group such as a methoxy group and an ethoxy group, and a C1 to C5 optionally branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of the halogen atom of the C1 to C5 optionally branched alkyl group optionally substituted with a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, etc.
Examples of the cycloalkylene group represented by A in formula (Ib) include preferably a C3 to C6 cycloalkylene group such as a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,1-cyclopentylene group, and a 1,1-cyclohexylene group, more preferably a 1,1-cyclopropylene group and a 1,2-cyclopropylene group. Preferable examples of the alkenylene group of the alkenylene group optionally substituted with a lower alkyl group include preferably a C2 to C4 alkenylene group such as a vinylene group and a butadiene group, more preferably a butadiene group. Examples of the alkyl groups of the alkenylene group optionally substituted with a lower alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
Preferable examples of the alkylene group of the alkylene group optionally substituted with a hydroxy group or an alkoxy group represented by B in formula (Ib) include preferably a C1 to C6 optionally branched alkylene group such as a methylene group, a dimethylene group, a trimethylene group, a tetramethylene group, a methylmethylene group, and a cyclopropylmethylene group, particularly preferably a methylene group, a dimethylene group, a trimethylene group, a tetramethylene group, and a cyclopropylmethylene group. Preferable examples of the alkoxy group of the alkylene group optionally substituted with an alkoxy group include a C1 to C5 optionally branched alkoxy group such as a methoxy group and an ethoxy group. Further, the integer n of 1 to 5 of the group xe2x80x94NHCO(CH2)nxe2x80x94 is preferably 1 or 3.
Preferable examples of the halogen atom represented by Y or Z include a fluorine atom, a chlorine atom and a bromine atom. Preferable examples of the alkoxy group include a C1 to C5 optionally branched alkoxy group such as a methoxy group and an ethoxy group. Preferable examples of the alkyl group optionally substituted with a halogen atom include a C1 to C5 optionally branched alkyl group such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of the halogen atom of an alkyl group optionally substituted with a halogen atom include a fluorine atom, a chlorine atom and a bromine atom.
Among the compounds represented by the formula (I), particularly preferable examples are listed below: 
wherein, Ar represents an optionally substituted phenyl group and E, Y, and Z are the same as defined above.
Further, according to the present invention, there is provided a compound having the formula (Ixe2x80x2): 
wherein, Rxe2x80x2 is an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted benzoyl group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxyl group, or group xe2x80x94NHCO(CH2)nxe2x80x94, where n is an integer of 1 to 5, E is a connecting bond, an oxygen atom, or a methylene group, X is a hydroxyl group or a hydrogen atom provided that, when E is an oxygen atom or a methylene group, X is not a hydrogen atom, and Y and Z may be the same or different from each other and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom, provided that, when X is a hydrogen atom and R is an optionally substituted phenyl group or an optionally substituted phenoxy group, B is not an alkylene group, that, when X is a hydroxyl group and R is an optionally substituted phenoxy group, B is not an unsubstituted alkylene group, that, when X is a hydroxyl group, R is an optionally substituted phenyl group, and A is a connecting bond, B is not an unsubstituted alkylene group or group xe2x80x94NHCO(CH2)nxe2x80x94, and that, when X is a hydroxyl group, R is an optionally substituted phenyl group, and A is a cycloalkylene group, B is not a group xe2x80x94NHCO(CH2)nxe2x80x94 and its pharmaceutically acceptable salt.
Examples of the preferable substituent of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted benzoyl group represented by Rxe2x80x2 include a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom, a hydroxyl group, a C1 to C5 optionally branched alkoxy group such as a methoxy group and an ethoxy group, and a C1 to C5 optionally branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of the halogen atom of the C1 to C5 optionally branched alkyl group optionally substituted with a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, etc.
The preferable examples of the cycloalkylene group and the alkenylene group optionally substituted with a lower alkyl group represented by A, the preferable examples of the alkylene group optionally substituted with a hydroxyl group or an alkoxy group represented by B, the preferable examples of the integer n of the group xe2x80x94NHCO(CH2)nxe2x80x94, and the preferable examples of the halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom represented by Y or Z are the same as the A, B, n, Y, and Z in the above formula (I).
Preferable examples of the compound of the formula (Ixe2x80x2) include compounds where, in the formula (Ixe2x80x2), Rxe2x80x2, A, B, and X are selected from the group consisting of:
1) Rxe2x80x2 is an optionally substituted phenyl group, A is an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxy group, or a group xe2x80x94NHCO(CH2)nxe2x80x94, where n is an integer of 1 to 5, and X is a hydroxyl group;
2) Rxe2x80x2 is an optionally substituted phenyl group, A is a connecting bond or a cycloalkylene group, B is an alkylene group substituted with a hydroxyl group, and X is a hydroxyl group;
3) Rxe2x80x2 is an optionally substituted phenyl group, A is a connecting bond or a cycloalkylene group, B is a group xe2x80x94NHCO(CH2)nxe2x80x94, where n is an integer of 1 to 5, and X is a hydroxyl group or a hydrogen atom;
4) Rxe2x80x2 is an optionally substituted phenoxy group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group substituted with a hydroxyl group, and X is a hydroxyl group; and
5) Rxe2x80x2 is an optionally substituted benzoyl group, A is a connecting bond, a cycloalkylene group, or an alkenylene group optionally substituted with a lower alkyl group, B is an alkylene group optionally substituted with a hydroxyl group or an alkoxy group or a group xe2x80x94NHCO(CH2)nxe2x80x94, where n is an integer of 1 to 5, and X is a hydroxyl group or a hydrogen atom
and where further E is a connecting bond, an oxygen atom, or a methylene group, Y and Z may be the same or different from each other and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom.
The compounds having the formula (Ixe2x80x2) in the present invention include compounds having the formulas (Ixe2x80x2a) and (Ixe2x80x2b):
Formula (Ixe2x80x2a) 
where, Rxe2x80x2, A, B, E, Y, and Z are the same as defined above;
Formula (Ixe2x80x2b) 
where, Rxe2x80x2, A, B, Y, and Z are the same as defined above.
The compounds having the formulas (I) and (Ixe2x80x2) include isomers. The present invention includes all of the individual isomers and mixtures thereof. For example, in the formulas (I) and (Ixe2x80x2), when A is an alkenylene group optionally substituted with a lower alkyl group, there are two types of geometric isomers, that is, the (E)-form and (Z)-form, and when B is an alkylene group substituted with a hydroxyl group or an alkoxy group, there are a pair of optical isomers, and the compounds according to the present invention include individual isomers formed by all combinations of these and mixtures thereof.
In accordance with the present invention, there is further provided a compound having the formula (II): 
where, Exe2x80x2 is an oxygen atom or a methylene group, and Y and Z may be the same or different from each other and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom.
The compounds having the formulas (I) and (Ixe2x80x2) according to the present invention may be synthesized in, for example, the following manners. These methods will be successively explained below.
The compounds (Ia) and (Ixe2x80x2a) where, in the formulas (I) and (Ixe2x80x2), X is a hydroxyl group, can be obtained as follows: That is, the compound (IV) is obtained from a known starting substance (III) (step 1), then is converted to the compound (IIa) (step 2), which is then allowed to react with the compound (V) or (Vxe2x80x2) to obtain the compound (Ia) or (Ixe2x80x2a) (step 3). The compounds (Ia) and (Ixe2x80x2a) where B is an alkylene group substituted with a hydroxyl group are obtained from the compound (IIa) and compound (VI) or (VIxe2x80x2) (step 4). The compounds (Ib) and (Ixe2x80x2b) where, in the formula (I), E is a connecting bond and X is a hydrogen atom are obtained by a reaction of the compound (IIb), derived from the compound (IVxe2x80x2) (step 5), with the compound (V) or (Vxe2x80x2) (step 6). The compounds (Ib) and (Ixe2x80x2b) where B is an alkylene group substituted with a hydroxyl group are obtained from the compound (IIb) and the compound (VI) or (VIxe2x80x2) (step 7).
The compound(IV) may be synthesized from the known starting substance (III) by the following method: 
wherein, E, Y, and Z are the same as defined above, and D represents a benzyl group, a p-methoxybenzyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group, or an acetyl group.
That is, an aryl bromide derivative (III) is converted to a corresponding aryl Grignard reagent or aryl lithium reagent by the conventional method, then is allowed to react in tetrahydrofuran, diethylether, ethyleneglycol dimethylether, toluene, or another solvent not participating in the reaction at xe2x88x92100 to 50xc2x0 C., preferably xe2x88x9278xc2x0 C. to room temperature, with 1 to 1.5 equivalents of the known starting material N-benzyl-4-piperidone, N-(p-methoxybenzyl)-4-piperidone, N-tert-butoxycarbonyl-4-piperidone, N-ethoxycarbonyl-4-piperidone, or N-acetyl-4-piperidone for 1 to 6 hours so as to obtain the compound having the formula (IV).
The starting material (III) used in the reaction is a known compound or can be synthesized by a known method [L. Martin et al., J. Med. Chem., 22, 1347 (1979); J. -P. Genet et al., Tetrahedron Lett., 37, 3857 (1996); G. Faye Crr et al., J. Med. Chem., 40, 1179 (1997)]. For example, 4-bromodiphenylether, 4-bromophenylether, 4-bromo-4xe2x80x2-fluorodiphenylether, 4-bromo-3xe2x80x2-fluorodiphenylether, 4-bromo-2xe2x80x2-fluorodiphenylether, 3-bromo-4xe2x80x2-fluorodiphenyl-ether, 3-bromo-3xe2x80x2-fluorodiphenylether, 3-bromo-2xe2x80x2-fluorodiphenylether, 2-bromo-4xe2x80x2-fluorodiphenylether, 2-bromo-3xe2x80x2-fluorodiphenylether, 2-bromo-2xe2x80x2-fluorodiphenyl-ether, 2-bromodiphenylmethane, 3-bromodiphenylmethane, 4-bromodiphenylmethane, 2-bromo-4xe2x80x2-fluorodiphenylmethane, 3-bromo-4xe2x80x2-fluorodiphenylmethane, 4-bromo-4xe2x80x2-fluoro-diphenylmethane, 2-bromo-4xe2x80x2-chlorodiphenylmethane, 3-bromo-4xe2x80x2-chlorodiphenylmethane, 4-bromo-4xe2x80x2-chloro-diphenylmethane, 2-bromo-4xe2x80x2-methoxydiphenylmethane, 3-bromo-4xe2x80x2-methoxydiphenylmethane, 4-bromo-4xe2x80x2-methoxydiphenylmethane, 2-bromo-4xe2x80x2-trifluoromethyl-diphenylmethane, 3-bromo-4xe2x80x2-trifluoromethyldiphenyl-methane, 4-bromo-4xe2x80x2-trifluoromethyldiphenylmethane, 3-bromo-4-fluorodiphenylmethane, 3-bromo-4,4xe2x80x2-difluorodiphenylmethane, 3-bromo-4-fluoro-4xe2x80x2-chlorodiphenylmethane, 3-bromo-4-fluoro-4xe2x80x2-methoxydiphenylmethane, 3-bromo-4xe2x80x2-fluoro-4xe2x80x2-trifluoromethyldiphenylmethane, 3-bromo-4-methoxydiphenylmethane, 3-bromo-4-methoxy-4xe2x80x2-fluorodiphenylmethane, 3-bromo-4-methoxy-4xe2x80x2-chloro-diphenylmethane, 3-bromo-4,4xe2x80x2-dimethoxydiphenylmethane, 3-bromo-4-methoxy-4xe2x80x2-trifluoromethyldiphenylmethane, 5-bromo-2-methoxydiphenylmethane, 5-bromo-2-methoxy-4xe2x80x2-fluorodiphenylmethane, 5-bromo-2-methoxy-4xe2x80x2-chloro-diphenylmethane, 5-bromo-2,4xe2x80x2-dimethoxydiphenylmethane, 5-bromo-2-methoxy-4xe2x80x2-trifluoromethyldiphenylmethane, 4-bromobiphenyl, 4-bromo-2-fluorobiphenyl, 4-bromo-4xe2x80x2-fluorobiphenyl, 4-bromo-4xe2x80x2-methoxybiphenyl, 4-bromo-4xe2x80x2-methylbiphenyl, 4-bromo-4xe2x80x2-trifluoromethylbiphenyl, 4,4xe2x80x2-dibromobiphenyl, etc. can be used. Further, as the conditions for preparing the Grignard reagent and the organolithium reagent, the various methods described in the xe2x80x9cCompendium for Organic Synthesisxe2x80x9d (Wiley-Interscience: A Division of John Wiley and Sons Ltd.) etc. can be used.
The compound obtained from the above reaction can be used as is for the next step or, if necessary, can be used after purification by a conventional method such as recrystallization or column chromatography.
The compound (IIa) can be synthesized from the compound (IV) obtained in step 1: 
where, E, Y, and Z are the same as defined above, and Dxe2x80x2 is a benzyl group or a p-methoxybenzyl group.
The compound (IV) obtained in step 1 can be converted to the compound having the formula (IIa) by hydrogenation in ethyl acetate, methanol, ethanol, isopropyl alcohol, or another solvent not participating in the reaction in the presence of a catalytic amount of palladium carbon, palladium hydroxide, platinum, etc. at atmospheric pressure to 6 atmospheres. Further, in the reaction, acetic acid, hydrochloric acid, or other acid may be added, if necessary.
The compounds (Ia) and (Ixe2x80x2a) where X is a hydroxyl group in the formulas (I) and (Ixe2x80x2) can be synthesized by a reaction of the compound (V) or (Vxe2x80x2) with the compound (IIa) obtained in step 2. 
where, R, Rxe2x80x2, A, B, E, Y, and Z are the same as defined above, and W is a group which can be easily exchanged with an amino group.
That is, the compound (IIa) obtained in step 2 is heated and stirred in benzene, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, or another solvent not participating in the reaction, in the presence of triethylamine, diisopropylethylamine, pyridine, or another organic base or sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium hydrogencarbonate, potassium hydrogencarbonate, or another inorganic base, at room temperature to 150xc2x0 C., preferably room temperature to 100xc2x0 C., with 1.0 to.1.5 equivalents of the compound (V) or (Vxe2x80x2) to obtain the compound having the formula (Ia) or (Ixe2x80x2a). Further, in this reaction, if necessary, sodium iodide or tetrabutylammonium iodide may be added. W is a leaving group easily exchanged with an amino group. For example, a chlorine atom, a bromine atom, or other halogen atom, an alkylsulfonyloxy group such as a methanesulfonyloxy group, or an arylsulfonyloxy group such as a p-toluenesulfonyloxy group may be mentioned.
As the compound (V) or (Vxe2x80x2) used in this reaction, a commercially available or known compound or one which can be synthesized by a known method can be used. For example, methyl iodide, ethyl iodide, ethyl bromide, propyl bromide, cinnamyl bromide, 3-bromo-2-methyl-1-phenyl-1-propene, 4-fluorocinnamyl bromide, (2,3,4-trimethoxy)cinnamyl bromide, 1-bromo-3-phenylpropene, (1-bromoethyl)benzene, (2-bromoethyl)benzene, 4-methoxycinnamyl bromide, 2-(4-fluorophenyl)oxyethyl bromide, 2-phenyloxyethyl bromide, 4-(4-fluorophenyl)oxybutyl bromide, 4-phenyloxybutyl bromide, 2-phenyloxypropyl bromide, trans-(2-phenyl)cyclopropylmethyl bromide, 1-phenyl-1-cyclopropylmethyl bromide, 1-phenyl-1-cyclopropanemethyl bromide, 1-phenyl-1-cyclopentanemethyl bromide, phenacyl bromide, 2-bromo-4xe2x80x2-methoxyacetophenone, 2-bromo-4xe2x80x2-fluoroacetophenone, 2-bromo-4xe2x80x2-chloroacetophenone, 2-bromopropiophenone, 2-bromo-2xe2x80x24xe2x80x2-dimethoxyacetophenone, 2-bromo-2xe2x80x25xe2x80x2-dimethoxyacetophenone, 2-bromo-4xe2x80x2-methylacetophenone, 4-chlorobutyrophenone, 4-chloro-4,-fluorobutyrophenone, 2-bromomethyl-2-phenyl-1,3-dioxolane, 2-bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane, 2-bromomethyl-2-(4-chlorophenyl)-1,3-dioxolane, 2-bromomethyl-2-(4-methoxyphenyl)-1,3-dioxolane, 2-(1-bromoethyl)-2-phenyl-1,3-dioxolane, 2-bromomethyl-2-(4-methylphenyl)-1,3-dioxolane, 2-bromomethyl-2-(2,4-dimethoxyphenyl)-1,3-dioxolane, 2-bromomethyl-2-(2,5-dimethoxyphenyl)-1,3-dioxolane, 2,3,4-trimethoxybenzyl chloride, benzyl bromide, 4-fluorobenzyl bromide, 2-fluorobenzyl bromide, 3-fluorobenzyl bromide, 4-(trifluoromethyl)benzyl bromide, 2-(trifluoromethyl)benzyl bromide, 3-(trifluoromethyl)benzyl bromide, 2-bromo-1-indanone, 2-bromomethylbenzofuran, (2-bromo-1-hydroxyiminoethyl) benzene, 3-methoxybenzyl chloride, 4-methoxybenzyl chloride, cinnamyl chloride, (2-bromo-1-methoxyethyl)benzene, 1-(4-chlorophenyl)cyclobutanemethyl bromide, 1-(4-chlorophenyl)cyclopentanemethyl bromide, 1-(4-methoxyphenyl)cyclopentanemethyl bromide, (2-bromo-1,1-diethoxyethyl)benzene, N-(2,6-dimethylphenyl)-2-bromoacetamide, 2-bromo-N-(trans-2-phenylcyclopropyl) acetamide, N-(1-phenyl)cyclopropyl-2-bromoacetamide, N-(2,6-dimethylphenyl)-4-bromobutylamide, N-(2,4,6-trimethylphenyl)-4-bromobutylamide, N-phenyl-2-bromoacetamide, N-(2,6-diisoopropylphenyl)-2-bromoacetamide, N-(1-phenyl)cyclopropyl-2-bromoacetamide, etc. can be used.
Further, the compound where in the formula (Ixe2x80x2a) Rxe2x80x2 is an optionally substituted phenyl group, A is a connecting bond, and B is an alkylene group substituted with a hydroxyl group can be also synthesized by a reduction of the compound (Ixe2x80x2a) obtained in this step where Rxe2x80x2 is an optionally substituted benzoyl group, A is a connecting bond, and B is an alkylene group by a conventional method.
The compound (Iaxe2x80x2) or (Ixe2x80x2axe2x80x2) where A is a bond arm and B is an alkylene group substituted with a hydroxyl group in the formulas (Ia) and (Ixe2x80x2a) can be synthesized from the compound (IIa) obtained in step 2: 
where, R, Rxe2x80x2, E, Y, and Z are the same as defined above, and p is 0 or an integer of 1.
That is, it can be synthesized by a reaction of the compound (IIa) obtained in step 2 in a solvent not participating in the reaction, such as benzene, toluene, tetrahydrofuran, diethyl ether, ethyleneglycol dimethyl ether, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, at room temperature to 200xc2x0 C., preferably 50 to 150xc2x0 C., with 0.9 to 1.5 equivalents of the compound (VI) or (VIxe2x80x2) for 1 to 24 hours.
As the compound (VI) or (VIxe2x80x2) used in this reaction, a commercially available or known compound or one which can be synthesized by a known method can be used. For example, 1,2-epoxyethylbenzene, (R)-(+)-1,2-epoxyethylbenzene, (S)-(xe2x88x92)-1,2-epoxyethylbenzene, (1R, 2R)-(+)-1-phenylpropylene oxide, (1S, 2S)-(xe2x88x92)-1-phenylpropylene oxide, 1,2-epoxy-3-phenoxypropane, (R)-(xe2x88x92)-2-(benzyloxymethyl)oxirane), (S)-(+)-2-(benzyloxymethyl)oxirane, 2,3-epoxypropylbenzene, glycidyl 2-methylphenyl ether, 4-tert-butylphenyl-2,3-epoxypropyl ether, 4-chlorophenyl-2,3-epoxypropyl ether, 2,3-epoxypropyl-4-methoxyphenyl ether, (R)-(xe2x88x92)-1,2-epoxy-3-phenoxypropane, (S)-(+)-1,2-epoxy-3-phenoxypropane, etc. may be used.
Further, in this reaction, if necessary, one or a combination of a plurality of organic base such as triethylamine, diisopropylethylamine and pyridine, inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium hydrogencarbonate and potassium hydrogencarbonate, or metal salt such as sodium iodide, tetrabutylammonium iodide, lithium carbonate, lithium chloride, zinc bromide and magnesium bromide may be added.
The compound (IIb) can be synthesized from the compound (IVxe2x80x2) where E is a connecting bond among the compounds represented by the formula (IV) obtained in step 1. 
where, Y, Z, D, and Dxe2x80x2 are the same as defined above.
The compound (IVxe2x80x2) obtained in step 1 is treated under non-solvent conditions or in solvent not participating in the reaction such as tetrahydrofuran, diethyl ether, ethyleneglycol dimethylether, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, water, methanol and ethanol, at xe2x88x9220 to 150xc2x0 C., preferably 0 to 80xc2x0 C., with 1 to 20 equivalents of acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and other organic acids or hydrochloric acid, sulfuric acid, nitric acid, or other inorganic acids for 1 to 12 hours, or the compound (IVxe2x80x2) is reacted in solvent not participating in the reaction such as benzene, toluene, methylene chloride, chloroform, and carbon tetrachloride, if necessary, in the presence of triethylamine, pyridine, diisopropylethylamine, or other bases, at xe2x88x9220 to 150xc2x0 C., preferably 0 to 100xc2x0 C., with 1 to 5 equivalents of thionyl chloride, methanesulfonylchloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluene sulfonyl chloride, phosphorus oxychloride, or other acid chloride derivatives for 1 to 6 hours, and the subsequent acid treatment similar to the above, so as to obtain a compound having the formula (VII). Next, the compound (VII) is treated by a similar method as described in step 2 to obtain the compound of the formula (IIb).
The compounds obtained by the above reactions can be used, as they are, for the next step, but can also be used after purification if necessary by a conventional method such as recrystallization or column chromatography.
The compound (Ib) or (Ixe2x80x2b) where X is a hydrogen atom in the formula (I) or (Ixe2x80x2) can be synthesized by a similar method as described in step 3 from the compound (IIb) obtained in step 5 and the compound (V) or (Vxe2x80x2): 
where, R, Rxe2x80x2, A, B, Y, and Z are the same as defined above.
Among the compounds represented by the formulas (Ib) and (Ixe2x80x2b), the compound (Ibxe2x80x2) or (Ixe2x80x2bxe2x80x2) where A is a connecting bond and B is an alkylene group substituted with a hydroxyl group can be synthesized by a similar method as described in step 4 from the compound (IIb) obtained in step 5: 
where, R, Rxe2x80x2, Y, Z, and p are the same as defined above.
The isomers included in the compound having the formulas (I) and (Ixe2x80x2) of the present invention may be separated by conventional methods, for example, recrystallization, column chromatography, thin layer chromatography, high pressure liquid chromatography, or similar methods using optically active reagents.
The compound having the formulas (I) or (Ixe2x80x2) of the present invention may be dissolved in a suitable organic solvent, for example, ether, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, etc. and treated with an inorganic or organic acid to obtain the corresponding salt. Examples of the inorganic acid used here include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, periodic acid, etc. and examples of the organic acid include formic acid, acetic acid, butyric acid, oxalic acid, malonic acid, propionic acid, valeric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, etc.
The compound according to the present invention is low in toxicity. For example, the 50% lethal dosage LD50 of acute toxicity of the compound of Compound No. 17, calculated from the death rate up to 24 hours after intravenous injection of the drug into ddY mice (male, 6 weeks old) by a conventional method, was 32 mg/kg.
The compound having the formula (I) or (Ixe2x80x2) of the present invention is low in toxicity and can be used alone by itself, or if desired, can be prepared with other normal pharmaceutically allowable known and generally used carriers into preparations designed for the alleviation and treatment of symptoms due to ischemic diseases. For example, the effective ingredient can be administered orally or nonorally by itself or made into a capsule, tablet, injection, or other suitable preparation together with usually used excipients. For example, capsule preparations are prepared by mixing the original powder with lactose, starch or its derivatives, cellulose derivatives or other excipients and packing the mixture into gelatin capsules. Further, tablets can be prepared by adding and kneading in, in addition to said excipient, sodium carboxymethylcellulose, alginic acid, arabia gum, and other binders and water, if necessary granulating the same, then further adding talc, stearic acid, or other lubricants and preparing the final form using a usual compression tablet-making machine. At the time of non-oral administration using injection, the effective ingredient is dissolved together with a solubilizer in sterilized distilled water or sterilized physiological saline and sealed in an ampule to make the injection preparation. If necessary, a stabilizing agent, buffer, etc. may also be included.
The dosage of the pharmaceutical composition for the alleviation or treatment of ischemic diseases differs depending on various factors, for example, the symptoms, gravity of symptoms, age, and complications of the patient to be treated and depending on the route of administration, the form of the preparation, the frequency of administration, etc., but usually is 0.1 to 1000 mg/day/person, preferably 1 to 500 mg/day/person as an effective ingredient in the case of oral administration, and {fraction (1/100)} to xc2xd the amount of oral dosage in the case of non-oral administration. These amounts of dosages may be suitably changed in accordance with the age, symptoms, etc. of the patient.